Diterpenoids

Contents

• 1 Introduction

• 2 Acyclic and related diterpenoids

• 3 Bicyclic diterpenoids
  • 3.1 Labdanes
  • 3.2 Clerodanes and related diterpenoids

• 4 Tricyclic diterpenoids

• 5 Tetracyclic diterpenoids

• 6 Macrocyclic diterpenoids and their cyclization products
  • 6.1 Taxanes

• 7 Miscellaneous diterpenoids

• References

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Abstract

Covering 2001. Previous review: Nat. Prod. Rep., 2002, 19, 125.

The review covers the isolation and structures of diterpenoids including labdanes, clerodanes, pimaranes, abietanes, kauranes, gibberellins, cembranolides, taxanes and marine diterpenoids. The literature from January to December 2001 is reviewed and 140 references are cited.

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1 Introduction

This report follows the pattern of its predecessors.¹ The variety of diterpenoid structures has made them attractive targets for synthesis. Although synthesis is outside the scope of this review, nevertheless it is worth noting the number of synthetic endeavours which have been reported. The range of diterpenoid carbon skeleta also makes these natural products useful taxonomic markers. A computer-assisted approach to the chemotaxonomy of the Lamiaceae (Labiatae) using diterpenoid skeleta as a guide, has been reported.²

2 Acyclic and related diterpenoids

12,13-Dehydrogeranylgeraniol has been isolated³ as an anti-fungal and anti-oxidant agent from the aquatic plant, Saururus cernuus. (S)-12-Hydroxygeranylgeraniol derivatives have been found⁴ in an Atlantic collection of the brown alga, Bifurcaria bifurcata whilst the hedaol norditerpenes (e.g. hedaol A, 1) were found⁵ as cytotoxic constituents of a Sargassum species. Inconyzic acid 2 was obtained⁶ from Conyza incana. Examination of the sponge, Jaspis splendens afforded⁷ (+)-subersin 3 which is an inhibitor of 15-lipoxygenase. The phorbasins, e.g.4, were obtained⁸ from a Phorbas species of sponge.

3 Bicyclic diterpenoids

3.1 Labdanes

The readily available diterpenoid, larixol, which is isolated from larch oleoresin, has continued to be a useful starting material for diterpenoid partial synthesis. Syntheses of the perfumery constituent ambrox^® from larixol, labdanolic acid and sclareol have been reported.^9,10 The ent-labdane 5 has been obtained¹¹ from Sideritis argyrea (Labiatae). Dihydrogrindelic acid 6 was obtained¹² from Colophosphermum mopane (Leguminoseae) which is a tree that grows in the arid regions of South Africa. The corresponding aldehyde shows some cytotoxicity. 19-Hydroxygrindelic acid 7 was isolated¹³ from Grindelia integrifolia. Labdanes are widespread amongst the Compositae. Some glycosides, e.g.8, have been detected¹⁴ in the flowers of Baccharis medullosa. A number of Croton (Euphorbiaceae) species have been used in South-East Asian folk medicine. The labdanes 9 and 10 were isolated from C. joufra and C. oblongifolius respectively.^15,16 Some chlorinated labdane imides, known as the haterumaimides, e.g.11, were extracted from a marine ascidian Lissoclinum species.^17,18

Hedychium species have previously been the source of diterpenes. Extraction of H. villosum gave¹⁹ villosin 12. Pacovatinin A 13 was obtained²⁰ from the seeds of Renealmia exaltata (Zingiberaceae). Vitex rotundifolia (Verbenaceae) is widely distributed in Asia and its fruit, Viticus fructus, is used in folk medicine for the relief of pain. Examination of the fruit has given a number of labdanes exemplified by 14.²¹ The absolute stereochemistry of limonidilactone 15, which had been isolated from V. limonidifolia, has been established²² by the partial synthesis of its enantiomer from zamoranic acid 16. The Diels–Alder adduct 17 has been obtained²³ from Alpinia flabellata.

The interactions between aquatic plants and microalgae form an important facet of aquatic eco-systems. Investigations of the aquatic plant, Potamogeton natans in this context have afforded^24,25 the lactone 18 and its furan analogue. Cacofuran A, 19, has been obtained²⁶ from a Cacospongia species of sponge. 11α-Hydroxy-13-epimanoyl oxide has been detected²⁷ in extracts of the medicinal plant, Kyllinga erecta (Cyperaceae). Further examples of the ptychantins have been obtained²⁸ from the liverwort, Ptychanthus striatus. The biotransformation of ribenone 20 by the fungus, Mucor plumbeus leads to hydroxylation at C-1α, C-6 (α and β) and C-12β.²⁹

The secolabdane, rhizophorin A 21 has been obtained³⁰ from the roots of the tree, Rhizophora mucronata. The tumour inhibitory activity of the secolabdanes from Excoecaria agallocha has been examined.³¹

3.2 Clerodanes and related diterpenoids

Halima-1(10),14-dien-13-ol has been detected³² in the liverwort, Jungermannia infusca. Some halimanes, the vitetrifolins D–G, e.g. D 22, have been reported³³ in the fruit of the Asian medicinal plant, Vitex trifolia. The 14,15-dinorhalimane 23 is a minor diterpenoid in Halimium viscosum.³⁴

Assignments of the ¹H and ¹³C NMR spectra of the clerodanes have been reported.³⁵ The seeds of Hymenaea courbaril have been reinvestigated and the clerodane 24 has been reported.³⁶ The thrombin inhibitory constituents of Duranta repens include the clerodane 25.³⁷Croton eluteria (Euphorbiaceae) is a small tree which is indigenous to the Bahamas and which has been used in the treatment of fever. The constituents of the bark include the cascarillins B–D 26.³⁸ The porwenins A and B, e.g.27, have been obtained³⁹ from Portulaca okinawensis.

The X-ray crystal structure of amarisolide 28 from Salvia amarissima has been reported.⁴⁰ Examination of the hallucinogenic Mexican herb, Salvia divinorum, has afforded⁴¹ a further clerodane, salvinorin C 29. A number of clerodanes have been isolated from Scutellaria (Labiatae) species. The scuteruleins A–D, e.g.30, have been found⁴² in S. caerulea and hematochloridin 31 was obtained⁴³ from S. hematuchlora. Teughrebin 32 has been isolated⁴⁴ from Teucrium maghrebinum whilst 7α-acetoxy-7,8α-dihydrogesnerofolin was detected⁴⁵ in Salvia gesneraeflora. The structure–activity relationships of neoclerodanes as insect antifeedants has been examined⁴⁶ and the topic has recently been reviewed.⁴⁷

The cis-clerodane 33 has been obtained⁴⁸ as an anti-bacterial constituent of Cistus monspeiensis whilst the intrapetacins A and B 34, from the roots of Licania intrapetiolaris, have anti-fungal properties.⁴⁹ The Thai medicinal plant, Tinospora baenzigeri has attracted attention because of its antimalarial properties. Ring A of the clerodane structure has been cleaved, possibly via a hydroxy-epoxide, in the formation of baenzigeride B 35 which is a constituent of this plant.⁵⁰

4 Tricyclic diterpenoids

2α,18-Dihydroxysandaracopimaradiene has been obtained⁵¹ from the leaves of Guarea rhophalocarpa (Meliaceae). The powdered leaves and bark from this plant have been reported to control bleeding. 6β-Hydroxyisopimaric acid has been identified⁵² as an anti-bacterial constituent of the roots of Salvia caespitosa. The triol 36 has been isolated⁵³ from the bark of the Chinese tree, Dysoxylum hainanense (Meliaceae). The beneficial analgesic and anti-inflammatory activity of the root-bark of the Korean medicinal plant, Acanthopanax koreanum has been associated with acanthoic acid 37. The absolute stereochemistry of this diterpene has now been established⁵⁴ by synthesis. A revised structure 38, based on an X-ray crystal structure, has been proposed⁵⁵ for leucophleoxol from Acacia leucophloea. The pimarane 39 has been obtained⁵⁶ from Jatropha divaricata. Further examination of Orthosiphon stamineus has afforded⁵⁷ additional members of the orthosiphol series which possess anti-proliferative activity. The ring A secopimarane 40 from Salvia cinnabarina has been reported⁵⁸ to possess anti-spasmodic activity.

Further investigations of the tree, Taiwania cryptomedioides (Taxodiaceae), which is resistant to fungal decay, have yielded⁵⁹ some podocarpane quinones including 41. The abietane, centdaroic acid, 42, has been isolated⁶⁰ from the roots of Cedrus deodara. The 7(6→2)abeo-abietane, obtusanal 43 has been obtained⁶¹ from the heartwood of Chamaecyparis obtusa. The drypetenones, e.g.44, are more highly oxidized abietanes which have been obtained⁶² from Drypetes littoralis (Euphorbiaceae). Abietane diepoxides, e.g.45 with anti-tumour activity, have been isolated⁶³ from the cones of Larix kaempferi.

The Chinese medicinal herb, Salvia miltiorrhiza (Tan-shen) has been the source of the tanshinones. Their microwave assisted extraction from the herbal material has been described⁶⁴ and a number of oleoyl esters, e.g.46, have been reported.⁶⁵ Blephaein 47 has been obtained⁶⁶ from the roots of Salvia blepharochlaena. The structure of the dimer, hongencaotone 48 from S. prionitis has been established⁶⁷ by X-ray crystallography. Many of the leaf pigments of Coleus and Plectranthus species (Labiatae) are diterpenoid quinones. Examination⁶⁸ of the ornamental medicinal plant, Coleus blumei gave the highly oxidized phenol 49. The rearranged abietane 50, which has anti-oxidative properties, has been obtained⁶⁹ from the leaves of Plectranthus nummularius. The 1β-hydroxycryptotanshinone 51 has been found⁷⁰ amongst the constituents of the roots of Perovskia abrotanoides. 7-Oxoabieta-9,12,14-triene, which was isolated⁷¹ from the roots of Salvia amplexicaulis, has been reported to have vasodepressor activity.

A further anti-fungal cassane quinone methide, 52, has been isolated⁷² from the roots of Bobgunnia madagascariensis. Plants belonging to the genus Caesalpinia (Leguminosae) have proven to be a rich source of cassane furanoditerpenes. There have been a number of reports on the constituents of Caesalpinia minax, a shrub used in Chinese folk medicine as ‘kushilian’ for the treatment of fever. The structure of caesalmin A 53 was established by X-ray crystallography.⁷³ Caesalmin C 54 possesses anti-viral activity⁷⁴ whilst the rearranged vouacapane, spirocaesalmin 55 exhibited⁷⁵ significant activity against the respiratory syncytial virus, a pathogen responsible for a number of respiratory infections.

The X-ray crystal structures of jolkinolide D 56⁷⁶ from Euphorbia jolkini and of the secochinane 57⁷⁷ from Juniperus chinensis varn. kaizuka have been published.

5 Tetracyclic diterpenoids

Continuing investigations of Trypterygium wilfordii have yielded some further diterpenoids. Extracts of the roots are used in folk medicine for the treatment of rheumatoid arthritis and other inflammatory diseases. The ethoxyacetal 58 has been obtained⁷⁸ from the ‘T_π’ extract. Modification of the readily available ent-kaurene, linearol, ent-3β,7α,18-trihydroxykaur-16-ene gave⁷⁹ a series of derivatives amongst which the 7,18-ditiglate ester possessed quite high insect anti-feedant activity. ent-7β,18-Dihydroxy-15-oxokaur-16-ene has been isolated⁸⁰ from Croton tonkinensis. A ring A secokaurene, pierisformoside G 59 has been obtained⁸¹ from the leaves of Pieris formosa.

Many Isodon (Rabdosia) species are used in Chinese herbal medicines. These plants have continued to attract attention and have been the source of highly oxidized ent-kaurenes and ring B secokaurenes. New compounds which have been reported include pseurata G 60 from R. pseudo-irrorata,⁸² the taibaihenryiins, e.g.61, from I. henryi,⁸³ the xerophilusins, e.g.62, from I. xerophilus,^84,85 irroratin A 63 from I. irrorata,⁸⁶ and taibaijaonicain A 64 from I. japonica.⁸⁷ A number of these structures were established by X-ray crystallography. The crystal structure of nodosin 65, from R. serra, has been published.⁸⁸

Aphidicolin is a metabolite of the fungus Phoma betae. A range of diterpene hydrocarbons, including aphidicol-16-ene, have been detected⁸⁹ in the mycelial extract. The NMR data for the scopadulcins have been assigned.⁹⁰ The bio-transformation of stemodin by the fungus, Beauveria bassiana gave⁹¹ 2α,13,18-trihydroxystemodane. Some atisanes, e.g.66, which have been obtained⁹² from the liverwort, Lepidolaena clavigera possess cytotoxic and insecticidal activity.

A thorough GC MS study⁹³ of the gibberellins of Prunus persica (peach) seeds has led to the detection of novel lα-hydroxy- and 1,2-didehydrogibberellins. These include GA₁₁₈67 and GA₁₂₆68. GA₇₃ methyl ester 69 has been detected⁹⁴ as the antheridiogen in the fern Lygodium microphyllum. Gibberellin metabolism has continued to attract attention. The mono-oxygenases involved⁹⁵ in GA₁₂ and GA₁₄ biosynthesis in Gibberella fujikuroi and the metabolism of GA₁ and GA₃ in Prunus avium (sweet cherry)⁹⁶ are amongst the topics which have been studied.

6 Macrocyclic diterpenoids and their cyclization products

An NMR study of acutanol 70, a cembranoid from Sarcophyton acutangulum, has been reported.⁹⁷ The absolute configuration of the cembrane epoxide 71 has been established⁹⁸ by its partial synthesis from (+)-carvone. A number of cembranolides including 72 have been obtained⁹⁹ from the soft coral, Sinularia tenella. Pachyclavulariolide G 73 was isolated¹⁰⁰ from the soft coral, Pachyclavularia violacea.

A number of jatrophanes have been isolated from Euphorbia species including 74 from E. turczaninowii¹⁰¹ and euphosalicin 75 from E. salicifolia.¹⁰² The latter has multi-drug resistance reversing activity in cancers. The tricyclic salicifoline 76 has been isolated¹⁰³ from the same plant. A revised structure 77 has been proposed¹⁰⁴ for the myrsinane, decipinone B which was obtained from E. decipiens. Segetene A 78 has been isolated¹⁰⁵ from E. paralias. Neostellerin 79 has been reported¹⁰⁶ as a constituent of the Chinese plant, Stellera chamaejasme.

6.1 Taxanes

Recent advances in the studies of taxol^® and major advances in the genetics of taxol^® biosynthesis have been reviewed.^107,108 Verticillatriene 80 has been detected¹⁰⁹ in the essential oil of Boswellia carterii.

Although there are estimated to be about 400 naturally occurring taxoids that are known, new examples continue to be isolated. These include 7-acetyl-10-deacetyltaxol from Taxus canadensis needles,¹¹⁰81 from T. cuspidata,¹¹¹ some further taxumairols, e.g.82 from the stem bark of T. mairei,¹¹²83 from the Himalayan yew, T. wallichiana,¹¹³ taxuyunnanine P 84¹¹⁴ and dantaxusin A 85¹¹⁵ from T. yunnanensis. Methods for the large scale separation of taxanes from T. yunnanensis have been described.¹¹⁶ Taxinines NN3 86 and 4 have been reported¹¹⁷ to have multi-drug resistant tumour modulating activity. The crystal structure of the dimethyl sulfoxide solvate of 10-deacetylbaccatin III has been reported.¹¹⁸

7 Miscellaneous diterpenoids

The chabrolols, e.g.87, have been obtained¹¹⁹ from the soft coral, Nephthea chabroli. The prevesols, e.g.88, from the red alga Laurencia obtusa,¹²⁰ have structures that are reminiscent of bismonoterpenes. Further xenicanes including acalycixeniolide H 89 have been isolated¹²¹ from the gorgonian, Acalycigorgia inermis. Continuing investigations on the briaranes of the gorgonian, Briareum excavatum have been reported including work¹²² on brianthein A 90, which has been shown to reverse multi-drug resistance in human carcinomas, and on briaexcavatolides K 91.¹²³ Milolide A 92 has been obtained¹²⁴ from the octacoral, Briareum stechei.

Examination of the soft corals to obtain a plentiful supply of eleutherobin for preclinical evaluation as an anti-cancer drug led to the isolation of the anti-mitotic compound, caribaeorane 93 from the Caribbean soft coral, Erythropodium caribaeorium.¹²⁵ The pachyclavulariaenones A–C, e.g.94, have been obtained¹²⁶ from the soft coral, Pachyclavularia violaceae.

Dolabella-3,7,18-triene 95 was obtained,¹²⁷ along with some sesquiterpenes, from the essential oil of the rhizomes of Cyperus alopecuroides whilst the dolabellane 96 was isolated¹²⁸ from Clavularia inflata. 1,3,5,15-Valparatetraene 97 has been obtained¹²⁹ from Halimium viscosum. The hydrocarbon, cyatha-3,12-diene 98 has been detected¹³⁰ in the Basidiomycete, Hericium erinaceum where it is a possible intermediate in cyathin biosynthesis. Serpendione 99 has been obtained¹³¹ from Hypoestes serpens. The biotransformation of hypoestenone by the fungus, Mucor plumbeus has been examined.¹³²

Examination of the aerial parts of Azorella yareta (Umbelliferae) has yielded¹³³ the trichomonocidal diterpene 13β-hydroxyazorellane 100 together with mulinolic acid. Epipolone 101 has been isolated¹³⁴ from the sponge, Epipolasis reiswigi. The bromoditerpene 102 has been obtained¹³⁵ from the red alga, Laurencia luzonensis. Amongst the new spongiane diterpenes is zimoclactone B 103 which was isolated¹³⁶ from Spongia zimocca. The serrulatane, erogorgiaene 104 has been detected¹³⁷ in Pseudopterogorgia elisabethae. Continued thorough investigations of Persea indica (Lauraceae) for insecticides with the ryanodine skeleton has led to the isolation of garajonone 105.¹³⁸ An interrelationship between the triquinane diterpenes, laurenene and waihoensene has been reported.¹³⁹ Some C₂₃ compounds with the apianane skeleton, e.g.106, have been isolated¹⁴⁰ from the sage, Salvia officinalis.

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